Accumulating evidence suggests that tissue hypoxia and apoptosis play important roles in the malignant progression of brain tumors. We investigated the relationship of 14-3-3zeta (an apoptosis-related protein), HIF-1α, and VEGF immunohistochemistry, and evaluated the prognostic value of their expression in human brain gliomas. A semiquantitative analysis of the immunoreactivity scores (IRSs) of the 14-3-3zeta, HIF-1α, and VEGF proteins was performed in 27 patients with various grades of gliomas. The IRS of 14-3-3zeta increased with tumor grade, with grade IV gliomas having the highest score (P < 0.05). Similar results were found for the IRSs of HIF-1α and VEGF (P < 0.05). A significant positive correlation was found between the IRSs of 14-3-3zeta and HIF-1α, 14-3-3zeta and VEGF, and HIF-1α and VEGF (P < 0.001 for all). The survival time of HIF-1α in grade III and grade IV glioma patients with low IRSs (0-6) was significantly longer than that in such glioma patients with high IRSs (8-12) (P < 0.05). These data indicate that 14-3-3zeta, HIF-1α, and VEGF are involved in the same cascade of the malignant progression of gliomas. Further studies will elucidate their detailed role in the malignant progression of glioma, and will contribute to the development of a new treatment strategy for this lethal disease.